Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR(90), +/-dL/dt), and fura-fluorescence intensity change (DeltaFFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the (3)H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and DeltaFFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR(90), or +/- dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca(2+). Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.
Hypertension 2002 Jan
PMID:Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. 1179 81

Mechanical stress activates various hypertrophic responses, including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Stretch activated extracellular signal-regulated kinases partly through secreted humoral growth factors, including angiotensin II, whereas stretch-induced activation of c-Jun NH(2)-terminal kinases and p38 MAPK was independent of angiotensin II. In this study, we examined the role of integrin signaling in stretch-induced activation of p38 MAPK in cardiomyocytes of neonatal rats. Overexpression of the tumor suppressor PTEN, which inhibits outside-in integrin signaling, strongly suppressed stretch-induced activation of p38 MAPK. Overexpression of focal adhesion kinase (FAK) antagonized the effects of PTEN, and both tyrosine residues at 397 and 925 of FAK were necessary for its effects. Stretch induced tyrosine phosphorylation and activation of FAK and Src. Stretch-induced activation of p38 MAPK was abolished by overexpression of FAT and CSK, which are inhibitors of the FAK and Src families, respectively, and was suppressed by overexpression of a dominant-negative mutant of Ras. Mechanical stretch-induced increase in protein synthesis was suppressed by SB202190, a p38 MAPK inhibitor. These results suggest that mechanical stress activates p38 MAPK and induces cardiac hypertrophy through the integrin-FAK-Src-Ras pathway in cardiac myocytes.
Hypertension 2002 Feb
PMID:Integrins play a critical role in mechanical stress-induced p38 MAPK activation. 1184 90

We investigated whether upregulation of Src by Ang II leads to increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and whether these processes are associated with altered activation of C-terminal Src kinase (Csk), a negative regulator of Src. Furthermore, the role of epidermal growth factor receptor (EGFR) transactivation by angiotensin II (Ang II) was determined. Ang II-mediated c-Src phosphorylation was significantly greater (approximately 4-fold, P<0.01) in SHR than in Wistar-Kyoto rats (WKY). Ang II increased Csk phosphorylation 2-to 3-fold in WKY but not in SHR. Treatment of the cells with AG1478, a selective EGFR tyrosine kinase inhibitor, decreased Ang II-mediated c-Src phosphorylation, particularly in SHR. Phosphorylation of cortactin and Pyk2/focal adhesion kinase, Src-specific substrates, was increased by Ang II >3-fold, with significantly greater responses in SHR than in WKY (P<0.05). Ang II-induced ERK1/2 activation was significantly augmented (P<0.05) and sustained in VSMCs from SHR. PP2, a selective Src inhibitor, attenuated these effects and normalized the responses in SHR. Irbesartan, a selective Ang II type 1 receptor blocker, but not PD123319, a selective Ang II type 2 receptor blocker, inhibited Ang II actions. Our results demonstrate that c-Src phosphorylation and Src-dependent ERK1/2 signaling by Ang II are increased in VSMCs from SHR. These processes are associated with blunted Ang II-induced phosphorylation of Csk. EGFR transactivation contributes to Ang II-mediated Src-dependent ERK1/2 signaling. In conclusion, altered regulation of Ang II type 1 receptor-activated c-Src by Csk may be an important upstream modulator of abnormal ERK1/2 signaling in VSMCs from SHR.
Hypertension 2002 Feb
PMID:Increased angiotensin II-mediated Src signaling via epidermal growth factor receptor transactivation is associated with decreased C-terminal Src kinase activity in vascular smooth muscle cells from spontaneously hypertensive rats. 1188 94

Elevated blood pressure is associated with varying degrees of arterial growth and remodeling. The mechanisms by which mechanical stress is converted into cellular alteration have yet to be fully elucidated. Our laboratory has demonstrated that Src tyrosine kinases and the extracellular signal-regulated kinase subtype of the mitogen-activated protein kinase family mediate pressure-induced c-fos expression in rat mesenteric arteries. Others have reported involvement of integrin and growth factor receptor signaling pathways. Our goal was to determine the role of Src, focal adhesion kinase (FAK), and platelet-derived growth factor (PDGF) receptor signaling in the upstream initiation of these events. Pairs of rat mesenteric arteries were pressurized to 90 mm Hg (control), and then one was raised to 140 mm Hg for 1, 3, or 5 minutes. Western blotting revealed that Src-pY(418) was elevated 2.4-fold over control values at 1 minute and 2.8-fold at 3 minutes and returned to control at 5 minutes. Significant FAK-Y(397) phosphorylation was observed only after 3 and 5 minutes of pressure stimulus and was blocked entirely by Src inhibition. Src-pY(215) activity (associated with PDGF receptor activation) does not seem to be involved at any of the time points tested. These data demonstrate that Src-Y(418) autophosphorylation is an early event in pressure mechanotransduction and leads to activation of FAK-Y(397). This finding suggests that Src may be the messenger that initiates and propagates the cellular growth response to pressure stimulus, and FAK is one of its downstream targets. Src phosphorylation due to PDGF receptor activation does not seem to be involved in the initial response.
Hypertension 2002 Feb
PMID:Src autophosphorylation is an early event in pressure-mediated signaling pathways in isolated resistance arteries. 1188 98

The purpose of this study is to examine the regulation of blood pressure and fluid and electrolyte homeostasis in mice overexpressing angiotensin II (Ang-II) in the brain and to determine whether there are significant physiologic differences in Ang-II production in neurons or glia. Therefore, we generated and characterized transgenic mice overexpressing human renin (hREN) under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice expressing human angiotensinogen (hAGT) under the control of the same promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice exhibited the highest hREN mRNA expression in the brain and had undetectable levels of hREN protein in the systemic circulation. In the brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice overexpressing both hREN and hAGT transgenes in either glia or neurons were moderately hypertensive. In the glia-targeted mice, blood pressure could be corrected by intracerebroventricular injection of the Ang-II type 1 receptor antagonist losartan, and intravenous injection of a ganglion blocking agent, but not an arginine vasopressin V1 receptor antagonist, lowered blood pressure. These data suggest that stimulation of Ang-II type 1 receptors in the brain by Ang-II derived from local synthesis of renin and angiotensinogen can cause an elevation in blood pressure via a mechanism involving enhanced sympathetic outflow. Glia- and neuron-targeted mice also exhibited an increase in drinking volume and salt preference, suggesting that chronic overexpression of renin and angiotensinogen locally in the brain can result in hypertension and alterations in fluid homeostasis.
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PMID:Glia- and neuron-specific expression of the renin-angiotensin system in brain alters blood pressure, water intake, and salt preference. 1208 69

Activation of the local and systemic renin-angiotensin system is directly and indirectly involved in mechanisms of vascular remodeling during chronic hypertension. This study investigated the effect of angiotensin II (AII) on rat vascular smooth muscle cell (VSMC) migration towards platelet-derived growth factor-BB (PDGF-BB) in vitro. Pre-treatment with AII (1 microM) for 48 or 72 h induced a significant increase in PDGF-BB-directed migration by 77 +/- 21 % and 58 +/- 24 %, respectively (both p < 0.01). This effect was concentration dependent and inhibited by the selective angiotensin receptor type I (AT(1)) blocker DUP 753. PDGF-directed migration of VSMCs was significantly inhibited by antibodies against beta(3)-and beta(5)-integrins, indicating an important role of these integrins in VSMC migration. However, AII augmented migration was not accompanied by an increased expression of beta(3)- and beta(5)-integrin mRNA and protein levels in VSMCs. Inhibition of the mitogen-activated protein kinase ERK 1/2 with PD 98059 (30 microM) completely abolished the effect of AII on PDGF-BB-directed VSMC migration (p < 0.01). The proline-rich tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK) are cytoskeleton-associated protein kinases participating in integrin-dependent signaling. Therefore, expression and phosphorylation of these kinases was determined 48 h after AII treatment, revealing a significant increase in Pyk2 and FAK protein levels (up to 2-fold, both p < 0.05) and increased phosphorylation of Pyk2 (2-fold, p < 0.05) and ERK 1/2 (4-fold, p < 0.05) as compared to controls. Furthermore, immunofluorescence and Western blot analysis demonstrated a translocation of Pyk2 from the plasma membrane to the cytosol, as well as a perinuclear enrichment of ERK 1/2 protein 48 h after AII treatment. In conclusion, our data suggest that changes in the levels of Pyk2 and ERK 1/2 phosphorylation, responsible for integrin-dependent signaling, as well as their subcellular translocation are important for the enhanced chemotactic response of VSMCs after AII pre-treatment.
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PMID:Angiotensin II-augmented migration of VSMCs towards PDGF-BB involves Pyk2 and ERK 1/2 activation. 1211 Oct 44

Proline-rich tyrosine kinase 2 (PYK2) is a member of the focal adhesion kinase (FAK) family of nonreceptor protein tyrosine kinases. PYK2 has been implicated in linking G protein-coupled receptors to activation of mitogen-activated protein kinase cascades and cellular growth in a variety of cell types. To determine whether PYK2 expression and phosphorylation is altered in left ventricular (LV) myocardium undergoing LV hypertrophy (LVH) and heart failure in vivo, suprarenal abdominal aortic coarctation was performed in 160-g male Sprague-Dawley rats. Immunohistochemistry and Western blotting were performed on LV tissue 1, 8, and 24 wk after aortic banding. Aortic banding produced sustained hypertension and gradually developing LVH. PYK2 levels were increased 1.8 +/- 0.2-, 2.7 +/- 0.6-, and 2.0 +/- 0.2-fold in 1-, 8-, and 24-wk banded animals compared with their respective sham-operated controls. The increase in PYK2 expression was paralleled by an increase in PYK2 phosphorylation, both of which preceded the development of LVH. Immunohistochemistry revealed that enhanced PYK2 expression occurred predominantly in the cardiomyocyte population. Furthermore, there was a high degree of correlation (R = 0.75; P < 0.001) between the level of PYK2 and the degree of LVH in 24-wk sham and banded animals. In contrast, FAK levels and FAK phosphorylation were not increased before the development of LVH. However, there was a high degree of correlation (R = 0.68; P < 0.001) between the level of FAK and the degree of LVH in 24-wk sham and banded rats. There was also a significant increase in the ratio of phosphospecific anti-FAK to FAK at this time point. These data are consistent with a role for PYK2 in the induction of pressure overload-induced cardiomyocyte hypertrophy, and suggest that PYK2 and FAK have distinctly different roles in LVH progression.
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PMID:PYK2 expression and phosphorylation increases in pressure overload-induced left ventricular hypertrophy. 1212 18

Angiotensin II (Ang II) is a multifunctional hormone that influences the function of cardiovascular cells through a complex series of intracellular signaling events initiated by the interaction of Ang II with AT1 and AT2 receptors. AT1 receptor activation leads to cell growth, vascular contraction, inflammatory responses and salt and water retention, whereas AT2 receptors induce apoptosis, vasodilation and natriuresis. These effects are mediated via complex, interacting signaling pathways involving stimulation of PLC and Ca2+ mobilization; activation of PLD, PLA2, PKC, MAP kinases and NAD(P)H oxidase, and stimulation of gene transcription. In addition, Ang II activates many intracellular tyrosine kinases that play a role in growth signaling and inflammation, such as Src, Pyk2, p130Cas, FAK and JAK/STAT. These events may be direct or indirect via transactivation of tyrosine kinase receptors, including PDGFR, EGFR and IGFR. Ang II induces a multitude of actions in various tissues, and the signaling events following occupancy and activation of Ang receptors are tightly controlled and extremely complex. Alterations of these highly regulated signaling pathways may be pivotal in structural and functional abnormalities that underlie pathological processes in cardiovascular diseases such as cardiac hypertrophy, hypertension and atherosclerosis.
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PMID:Recent advances in angiotensin II signaling. 1221 72

It remains undetermined whether continuous endothelial nitric oxide (NO) overexpression exerts angiogenic action. We surgically induced hindlimb ischemia in transgenic mice overexpressing endothelial NO synthase in the endothelium (eNOS-Tg) and studied neocapillary formation, ischemia-induced vascular endothelial growth factor (VEGF) expression, cGMP accumulation, and Akt/PKB signaling. Laser Doppler imaging revealed a markedly increased recovery of blood perfusion in ischemic limbs of eNOS-Tg mice (44% increase) compared with that in wild-type mice. Angiography showed a marked increase in basal and ischemia-induced collateral vessel formation in eNOS-Tg mice. Basal capillary densities and tissue cGMP levels were increased in eNOS-Tg mice (1.8-fold and 1.6-fold versus wild-type mice, respectively). Ischemia-induced neocapillary formation and cGMP accumulation were markedly increased in eNOS-Tg mice (3.6-fold and 4.1-fold versus preischemia levels, respectively), whereas those in wild-type mice were much less (1.8-fold and 1.5-fold, respectively). Basal and time-dependent VEGF expression in ischemic muscles did not differ between eNOS-Tg and wild-type mice. Basal and VEGF-mediated Akt phosphorylation in aortas was similar between eNOS-Tg and wild-type mice. Aortic basal eNOS expression was increased 3.3-fold, and VEGF-mediated eNOS phosphorylation was markedly induced in aortas of eNOS-Tg compared with preischemia levels (4.2-fold), whereas much smaller changes were observed in wild-type mice (1.8-fold increase). Our study demonstrates that overexpression of eNOS protein causes a marked increase in neocapillary formation in response to tissue ischemia without affecting ischemia-induced VEGF expression or VEGF-mediated Akt phosphorylation.
Hypertension 2003 Jan
PMID:Enhancement of ischemia-induced angiogenesis by eNOS overexpression. 2370 57

This minireview is an update of a 1997 review on erythropoietin (EPO) in this journal. EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1alpha). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A(2), and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A(2) pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular smooth muscle cell proliferation. Recombinant human EPO (rHuEPO) is currently being used to treat patients with anemias associated with chronic renal failure, AIDS patients with anemia due to treatment with zidovudine, nonmyeloid malignancies in patients treated with chemotherapeutic agents, perioperative surgical patients, and autologous blood donation. A novel erythropoiesis-stimulating factor (NESP, darbepoetin) has been synthesized and when compared with rHuEPO, NESP has a higher carbohydrate content (52% vs 40%), a longer plasma half-life, the amino acid sequence differs from that of native human EPO at five positions, and has been reported to maintain hemoglobin levels just as effectively in patients with chronic renal failure as rHuEPO at less frequent dosing. The use of rHuEPO and darbepoetin to enhance athletic performance is officially banned by most sports-governing bodies because the excessive erythrocytosis can lead to increased thrombogenicity and can cause deep vein, coronary, and cerebral thromboses.
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PMID:Erythropoietin: physiology and pharmacology update. 1252 67


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